PROJECT SUMMARY The overall goal of this proposed research is to elucidate the mechanisms that may confer increased vulnerability to Alzheimer?s disease (AD)-related cognitive decline in females, using state-of-the-art multi-modal neuroimaging, in both middle and older-aged adults. Females are often reported to exhibit greater rates of clinical progression to AD dementia than males. The applicant?s preliminary data suggest, however, that minimal sex differences exist in amyloid burden, implying other pathophysiologic mechanisms, such as tau, may influence subsequent elevated risk of cognitive decline in older females. It is also critical to investigate the early emergence of sex differences in AD biomarker accumulation during midlife, when sex and hormonal factors may have a particular impact. During the K99 phase, the first aim will identify sex differences in AD neuroimaging biomarkers of amyloid, tau and neurodegeneration in clinically-normal older adults. The second aim will determine relationships between sex and baseline AD biomarkers on longitudinal rates of cognitive decline in the same sample. The primary hypothesis, based on preliminary data, is that women will demonstrate greater tau burden, neurodegeneration and rates of cognitive decline despite similar levels of amyloid burden, likely due to an interaction between sex and APOE genotype. To accomplish these goals, the applicant will leverage existing strengths in statistical modeling and cognitive neuroscience to gain expertise in four critical areas of training: (1) multimodal imaging, (2) data harmonization, (3) longitudinal modeling, and (4) sex biology. With the development of these skills, the applicant will be well positioned in the R00 phase to conduct the final aim: to investigate sex differences in AD biomarker accumulation in middle-aged adults. In addition, the candidate will focus on the influence of hormonal stage (pre-menopause, perimenopause, and menopause) on rates of AD biomarker accumulation relative to age-matched males. A highly innovative component of this project is the use of multimodal neuroimaging (positron emission tomography (PET) and magnetic resonance imaging) and genetics to understand the mechanisms underpinning greater female risk for AD. The proposed study will provide some of the first insights into sex-differences in regional tau-PET burden in preclinical AD in middle and older-age adults. To boost statistical power for detecting sex effects in the K99 phase, data will be harmonized across three well-characterized, longitudinal cohorts of older adults (60-90 years). For the R00 phase, a similar approach will be employed to harmonize data across three longitudinal cohorts of middle-aged adults (40-65 years). Elucidating sex-specific effects on Alzheimer?s disease (AD) risk across the lifespan has far-reaching consequences for understanding the biological mechanisms that catalyze AD risk, and also for better powering clinical trials to identify those are at greatest risk. For the applicant, this program will enhance a rapid transition to independence using a short period of intensive training and mentorship, which will seamlessly intertwine with the aims of this proposed research direction.